Multiscale Modeling of Blood Flow and Platelet Mediated Thrombosis

血流和血小板介导的血栓形成的多尺度建模

• 批准号: 9032130
• 负责人: DANNY BLUESTEIN
• 金额: $ 68.94万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032130
• 关键词: Accounting; Address; Adhesions; Adopted; Agonist; Algorithms; Anticoagulation; Antiplatelet Drugs; Arteries; Benchmarking; Binding; Biochemical; Biology; Biomechanics; Blood; Blood Circulation; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cause of Death; Cereals; Cessation of life; Chemicals; Clinical; Coagulation Process; Code; Communities; Complex; Computer Simulation; Coronary Arteriosclerosis; Coupled; Coupling; Cytoplasm; Cytoskeleton; Data; Databases; Deposition; Development; Devices; Engineering; Evaluation; Event; Experimental Models; Filopodia; Growth; Health Care Costs; Hemostatic Agents; High Performance Computing; Hybrids; In Vitro; Lead; Length; Life; Liquid substance; Measurement; Measures; Mechanics; Mediating; Membrane; Methodology; Modeling; Molecular; Outcome; Patients; Pattern; Platelet Activation; Platelet aggregation; Process; Property; Proteins; Protocols documentation; Pseudopodia; Quality of life; Risk; Scheme; Series; Shapes; Software Tools; Stimulus; Stress; Surface; Technology; Therapeutic; Therapeutic Embolization; Thrombin; Thrombosis; Thrombus; Time; Tissues; Translating; Vascular Diseases; base; biomechanical model; burden of illness; computing resources; cost; design; fluid flow; hemodynamics; improved; injured; innovation; interest; men who have sex with men; microscopic imaging; molecular dynamics; molecular scale; mortality; multi-scale modeling; multidisciplinary; nanoscale; next generation; novel; particle; public health relevance; receptor; research study; response; shear stress; simulation; tool; working group

 DESCRIPTION (provided by applicant): Cardiovascular diseases remain the leading cause of death in the developed world, accounting for near 30% of all deaths globally and 35% in the US annually. Coronary artery disease (CAD) with its associated thrombotic risk is responsible for 1 of 6 deaths in the US. Coincidentally, implantable blood recirculating devices, which have provided lifesaving solutions to patients with severe cardiovascular diseases, are burdened with thrombosis and thromboembolic complications, mandating complex life-long anticoagulation. The mechanisms underlying vascular disease processes and device-related thrombotic complications are intertwined. Thrombosis in vascular disease is potentiated by the interaction of blood constituents with an injured vascular wall and the non-physiologic flow patterns generated in cardiovascular pathologies initiate and enhance the hemostatic response by chronically activating the platelets. Similarly, device thrombogenicity is induced by pathological flow fields and contact with foreign surfaces. Upon activation platelets undergo complex biochemical and morphological changes. The coupling of the disparate spatio-temporal scales between molecular level events and the macroscopic transport represents a major modeling and computational challenge, which requires a multidisciplinary integrated multiscale numerical approach. Continuum approaches are limited in their ability to cover the smaller molecular mechanisms such as filopodia formation during platelet activation. Utilizing molecular dynamics (MD) to cover the multiscales involved is computationally prohibitive. In this application we offer to develop a comprehensive state-of-the-art multiscale numerical methodology that will be able to bridge the gap between the macroscopic transport and the ensuing molecular events. We will use an integrated Dissipative Particle Dynamics (DPD) and Coarse Grained Molecular Dynamics (CGMD) approach that allows platelets to continuously change their shape and synergistically activate by a biomechanical transductive linkage chain, interact with other blood constituents and clotting factors, aggregate, and interact and adhere to the blood vessels and devices. In this multiscale model, a mechanotransduction CGMD bottom platelet activation model is embedded into a DPD blood flow top model. The dynamic stresses of the macroscale model will be interactively translated to the micro to nanoscale model of the intra-platelet associated intracellular events. The model predictions will be validated in vitro in a carefully designed set of experiments. This will be achieved according to the following specific aims: We will develop a mechanotransduction model of platelet mediated thrombosis where a top/macro-scale model of flow-induced thrombogenicity using DPD at the µm-length and ms-time scales, in which multiple flowing platelets interact with each other and blood vessel walls or devices, will be fully coupled with a bottom/micro-scale model using CGMD at the nm-length and ps-time scales, in which platelets with multiple intracellular constituents evolve during activation as platelet lose their quiescent discoid shape and filopodia grow. The top and bottom models will be interfaced such that the hemodynamics will interactively respond to platelet shape change upon activation and platelet aggregation and thrombus is formed. The effect of modulating platelet mechanical properties via antiplatelet agents will be modeled as well. All model aspects will be validated in vitro in a series of carefully designed experiments characterizing the mechanical properties of platelets and using blood flow experiments where conditions leading to flow induced platelet activation will be replicated, as well as experiments where platelet-wall and platelet device interactions will be measured and where platelets will be pretreated with modulating agents. These data will be used to fine tune the large number of model parameters involved in this multiscale simulation and for validating the model predictions. An independent 3rd party evaluation of the model credibility is also included as an integral part of the project. e will also concentrate on the development of efficient algorithms adapted for ultra-scalable large HPC clusters to reduce prohibitive computation costs, so as to bring such ambitious large multiscale simulations within the reach of the multiscale modeling community at large and enable to adopt it to other relevant modeling needs and interests. To further enable these technologies, large sharable data base will be created where software tools, numerical codes, model and experimental data and protocols will be deposited and guidance will be provided for using them. The leaders of the project will be active in various MSM consortium working groups to further disseminate the project outcomes and share them with the modeling community. The methodology proposed represents a paradigm shift in the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. Predicting the progression of arterial thrombosis under circulation conditions, providing tools for improved pharmacological management as compared to existing empirics-based treatments, and providing a modeling tool for developing the next generation of devices with reduced thrombogenicity may lead to reduced mortality rates, improved patients' quality of life, and an overall reduction of the financial burden of the ensuing healthcare costs.

 描述(申请人提供)：心血管疾病仍然是发达国家的主要死亡原因，占全球死亡人数的近30%，在美国每年占35%。在美国，冠状动脉疾病(CAD)及其相关的血栓风险导致了六分之一的死亡。巧合的是，植入式血液循环装置为患有严重心血管疾病的患者提供了挽救生命的解决方案，但却背负着血栓形成和血栓栓塞并发症的负担，需要复杂的终身抗凝。血管疾病过程的潜在机制和设备相关的血栓并发症是相互交织的。血管疾病中的血栓形成是由于血液成分与受损的血管壁相互作用而加强的，而心血管病理中产生的非生理性流动模式通过慢性激活血小板来启动和增强止血反应。同样，设备的血栓形成是由病理性的流场和与异物表面的接触引起的。激活后，血小板会经历复杂的生化和形态变化。分子水平事件和宏观输运之间不同的时空尺度之间的耦合是一个重大的建模和计算挑战，这需要一种多学科综合的多尺度数值方法。连续体方法在覆盖较小的分子机制方面是有限的，例如在血小板激活过程中形成丝状足。利用分子动力学(MD)来覆盖所涉及的多尺度在计算上是不可能的。在此应用程序中，我们提供 开发一种综合的最先进的多尺度数值方法，能够弥合宏观输运和随后的分子事件之间的差距。我们将使用耗散粒子动力学(DPD)和粗粒分子动力学(CGMD)相结合的方法，允许血小板不断改变其形状，并通过生物力学传导连锁链协同激活，与其他血液成分和凝血因子相互作用，聚集，并相互作用并附着在血管和设备上。在这个多尺度模型中，将机械转导CGMD底部血小板激活模型嵌入到DPD血流顶部模型中。宏观模型的动态应力将被交互地转化为与血小板内相关的细胞内事件的微观到纳米尺度的模型。这些模型的预测将在一系列精心设计的实验中得到体外验证。我们将根据以下具体目标实现这一目标：我们将开发一个血小板介导的血栓形成的机械转导模型，在该模型中，使用微米长和毫秒时间尺度的DPD建立流动诱导血栓形成的顶层/宏观模型，在该模型中，多个流动的血小板相互作用，血管壁或装置，与在纳米长度和PS时间尺度使用CGMD的底层/微尺度模型完全耦合，在该模型中，含有多种细胞内成分的血小板在激活过程中随着血小板失去其静止的盘状形状和丝状孔道生长而演化。顶部和底部模型将连接在一起，这样血液动力学将对激活时的血小板形状变化做出交互反应，并形成血小板聚集和血栓。通过抗血小板药物调节血小板机械性能的效果也将被模拟。所有模型的所有方面都将在体外通过一系列精心设计的实验来验证，这些实验表征了血小板的机械性能，并使用了血液流动实验，其中导致流动诱导的血小板激活的条件将被复制，以及在 将测量血小板装置的相互作用，并在哪里用调节剂对血小板进行预处理。这些数据将被用来微调这次多尺度模拟中涉及的大量模型参数，并用于验证模型预测。作为项目的一个组成部分，还包括对模型可信度的独立第三方评估。E还将专注于开发适用于超可伸缩大型HPC集群的高效算法，以降低令人望而却步的计算成本，以便将这种雄心勃勃的大规模多尺度模拟纳入整个多尺度模型界的能力范围内，并使其能够应用于其他相关的建模需求和兴趣。为进一步支持这些技术，将建立大型可共享数据库，其中将储存软件工具、数值代码、模型和实验数据以及协议，并将为其使用提供指导。该项目的领导人将积极参加各种MSM联盟工作组，进一步传播项目成果，并与模型界分享。所提出的方法代表了多尺度模拟这一新兴领域的范式转变，并将其应用于在工程和生物学的界面上解决复杂的临床问题。预测循环条件下动脉血栓形成的进展，提供与现有基于经验的治疗相比更好的药理学管理工具，并为开发具有更低致血栓活性的下一代设备提供建模工具，可能会降低死亡率，改善患者的生活质量，并总体上减轻随之而来的医疗成本的财政负担。